A novel mouse cDNA, Ikappabl, has been identified. IkappaBL was cloned from a chromosomal locus associated with susceptibility to UVB-induced immunosuppression, and is a leading candidate skin cancer susceptibility gene. DNA sequence analysis of Ikappabl indicates strong homology to the IkappaB family of transcriptional inhibitors. This family of regulators has long been regarded as a central factor in the elementary control of immune system development and activation. More recently, altered expression of IkappaB proteins has been implicated in the development of certain cancers, autoimmune diseases, and even heart disease. With a single exception; all IkappaB proteins are ubiquitously expressed. Preliminary data indicate that IkappaBL has a limited tissue expression. Studies are proposed to: (1) fully elucidate the tissue expression of the IkappaBL gene product, (2) demonstrate its physiological significance, and (3) determine the key regulatory elements responsible for its unique expression pattern. Anti-IkappaBL antibodies will be generated and used to study the physical characteristics and distribution of the protein by western blot and immunoprecipitation techniques, and a bacterial 2-hybrid system will be employed to identify proteins that interact with the IkappaBL gene product. Transfection experiments will be designed to study the basic function of this gene product and its effects on the regulation of other immunologically relevant genes. Lastly, a study of the Ikappabl gene promoter region will be undertaken by means of a luciferase reporter system in order to determine which promoter sequences and corresponding transcription factors are responsible for the differential tissue expression of the IkappaBL protein itself. To the principal investigator's knowledge, no other laboratory is investigating the function of the IMol gene. It is expected that several complementary inquiries will branch from this research including: studies of which genes and cell types are affected by IkappaBL; how IkappaBL is activated and inactivated; what biological processes are dependent or independent of IkappaBL; and what role, if any, does IkappaBL play in neoplasia and other disease states in mice as well as humans.